Rifaximin complexes

ABSTRACT

There is provided a complex comprising rifaximin and a complexing agent, wherein the complexing agent is a polyvinyl pyrrolidone (PVP) or a cyclodextrin. There is also provided a process for preparing the complex, a pharmaceutical composition including the complex and therapeutic uses of the complex.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to complexes of rifaximin and processesfor preparing such complexes.

BACKGROUND

Rifaximin is a semi-synthetic, rifamycin antimicrobial drug with invitro activity against Gram-positive, Gram-negative and anaerobicbacteria. It acts by inhibiting bacterial ribonucleic acid (RNA)synthesis. Rifaximin is chemically termed as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]-trienimino)benzofuro-[4,5-e]-pyrido-[1,2-a]-benzimidazole-1,15-(2H)-dione,25-acetate (I).

Rifaximin is used for treatment of travelers' diarrhea caused bynoninvasive strains of Escherichia coli.

WO2009137672 discloses a method of treating bowel disease (BD),comprising administering a gastrointestinal cleanser to a subject inneed thereof; and administering a therapeutically effective amount of anantibiotic.

Rifaximin was first disclosed in U.S. Pat. No. 4,341,785 which alsodiscloses a process for its preparation and a method for crystallizationof rifaximin by using suitable solvents or a mixture of solvents. Thispatent does not mention polymorphism of rifaximin.

U.S. Pat. No. 4,557,866, and its equivalent CA1215976, discloseprocesses for the preparation of rifaximin.

WO2007047253 discloses a pharmaceutical composition of hydroxybutenylcyclodextrins with antifungal azole compounds. However, this applicationdoes not provide any enabling methods nor proof of advantages of such acomplex.

WO2008035109 discloses the amorphous form of rifaximin.

U.S. Pat. No. 7,045,620, discloses various crystalline polymorphic formsof rifaximin which are termed as rifaximin α, rifaximin β and rifaximinγ. These polymorphic forms are characterized using X-ray powderdiffraction. According to U.S. Pat. No. 7,045,620, the presence of waterwithin the crystallization solvent plays an important role in crystalformation. Thus, rifaximin polymorphs undergo changes with a change inthe moisture content, and interconversion of one form to another occurswith an increase or decrease in the water content.

U.S. Pat. No. 7,045,620 further discloses rifaximin a which has a watercontent between 2.0% and 3.0%, rifaximin β which has a water contentbetween 5.0% and 6.0%, and rifaximin γ which is poorly crystalline andhas a water content between 1.0% and 2.0%.

EP1698630 discloses further polymorphic forms of rifaximin termed as δand ε. The stability of these forms also depends upon the water content.

However, all these forms are hygroscopic and they have a tendency tointerconvert from one to another. Thus, these forms are difficult tohandle as well as store and they require controlled conditions,specifically, humidity and temperature during handling and storage.

Thus, transformations of polymorphic forms of drug substances are ofgreat disadvantage, because they cause difficulties in fulfillingpharmaceutical requirements and specifications. The physicochemicalproperties of products that exhibit such polymorphic change varyaccording to the actual ratio of polymorphic forms. This causes furtherdifficulties while formulating the polymorphic forms into suitabledosage forms.

Also, as rifaximin is sparingly soluble in water, the formulationchemist finds it difficult to prepare a consistent formulation using theknown polymorphic forms. Hence, there is a need to prepare rifaximin ina form which is suitable for formulation and has increased solubilityand stability.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provideda form of rifaximin with enhanced solubility and stability. This form ofrifaximin is a complex comprising rifaximin and a complexing agent.

According to another aspect of the present invention, there is provideda complex comprising rifaximin and a complexing agent. Throughout thisspecification, this complex may be referred to as “the rifaximincomplex”. In an embodiment, the complex comprises solely rifaximin andthe complexing agent, i.e. no other components are present in thecomplex.

Advantageously, the complex of the present invention exhibits enhancedsolubility and stability, particularly compared to a physical mixture ofrifaximin and a complexing agent.

The complexing agent used in the present invention comprises a polyvinylpyrrolidone (PVP) or a cyclodextrin (CD).

In an embodiment, the complexing agent is a PVP. In an alternativeembodiment, the complexing agent is a CD.

In an embodiment, the complexing agent is not hydroxybutenylcyclodextrin or sulfonyl hydroxybutenyl cyclodextrin.

In an embodiment, the complexing agent is a PVP having a K-value rangingfrom K-15 to K-90. Suitably, the complexing agent is a PVP selected fromthe group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80,K-90 and K-120, preferably, K-25, K-30 or K-90. Typically, thecomplexing agent is PVP K-30.

In an embodiment, the complexing agent is an unmodified cyclodextrin. Inother words, the CD is a cyclic glucose oligosaccharide in which none ofthe hydroxyl groups has been modified. In an embodiment, the complexingagent is a cyclodextrin selected from the group consisting ofα-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, preferablyβ-cyclodextrin.

In an embodiment, the weight ratio of rifaximin to complexing agentranges from 20:1 w/w to 1:20 w/w. It is to be understood that “w/w”means by weight. Advantageously, the ratio of rifaximin to complexingagent ranges from 10:1 w/w to 1:2 w/w. Typically, the ratio of rifaximinto complexing agent ranges from 4:1 w/w to 1:2 w/w. The ratio may be 1:1w/w.

According to another aspect of the present invention, there is providedthe rifaximin complex characterized by having an intrinsic dissolutionprofile as shown in any one of FIGS. 1 to 8.

According to another aspect of the present invention, there is provideda process for preparing a complex comprising rifaximin and a complexingagent, the process comprising:

a) dissolving rifaximin in a solvent;b) adding the complexing agent to the rifaximin solution to form amixture;c) isolating the complex from the reaction mass obtained in step b).

In an embodiment, the complex comprises solely rifaximin and thecomplexing agent, i.e. no other components are present in the complex.

The complexing agent used in the process comprises a polyvinylpyrrolidone (PVP) or a cyclodextrin (CD).

In an embodiment, the complexing agent is a PVP. In an alternativeembodiment, the complexing agent is a CD.

In an embodiment, the complexing agent is a PVP having a K-value rangingfrom K-15 to K-90. Suitably, the complexing agent is a PVP selected fromthe group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80,K-90 and K-120, preferably, K-25, K-30 or K-90. Typically, thecomplexing agent is PVP K-30.

In an embodiment, the complexing agent is a cyclodextrin selected fromthe group consisting of α-cyclodextrin, β-cyclodextrin orγ-cyclodextrin, preferably β-cyclodextrin.

In an embodiment, the weight ratio of rifaximin to complexing rangesfrom 20:1 w/w to 1:20 w/w. It is to be understood that “w/w” means byweight. Advantageously, the ratio of rifaximin to complexing agentranges from 10:1 w/w to 1:2 w/w. Typically, the ratio of rifaximin tocomplexing agent ranges from 4:1 w/w to 1:2 w/w. The ratio may be 1:1w/w. Thus, according to another aspect of the present invention, thereis provided a complex comprising rifaximin and a complexing agent,wherein the weight ratio of rifaximin to complexing ranges from 20:1 w/wto 1:20 w/w, preferably from 10:1 w/w to 1:2 and more preferably from4:1 w/w to 1:2 w/w.

The rifaximin used in the process of the present invention may be in anypolymorphic form or in a mixture of any polymorphic forms.

The complexing agent may be added to the rifaximin solution as such orin the form of a solution with a solvent.

The solvent for the rifaximin may be selected from the group consistingof an ether, an alcohol, an ester, an aldehyde, a halogenated solvent, ahydrocarbon and mixtures thereof. Preferably, the solvent is an alcohol,for example methanol or ethanol. Typically, the solvent is ethanol.

The complexing agent may be added to the rifaximin in the form of asolution. In which case, the solvent for the complexing agent may beselected from the group consisting of an ether, an alcohol, an ester, analdehyde, a halogenated solvent, a hydrocarbon and mixtures thereof.Preferably, the solvent is an alcohol, for example methanol or ethanol.Typically, the solvent is ethanol.

Alternatively, the complexing agent may be added to the rifaximinsolution as such, i.e. not in the form of a solution.

Suitably, the isolation comprises concentrating the reaction massobtained in step b), and drying to obtain the isolated complex.

According to another aspect of the present invention, there is provideda complex prepared according to the process described above.

According to another aspect of the present invention, there is provideda complex comprising rifaximin and a complexing agent, which complexenhances at least one of the following:—

a) stabilization of rifaximin against degradation (e.g. hydrolysis,oxidation, etc)b) water solubilityc) dissolutiond) free flowability and non-hygroscopicitye) solubility, delivery and/or performancef) safe handling

According to yet another aspect of the present invention, there isprovided a rifaximin complex as described above for use in medicine.

According to yet another aspect of the present invention, there isprovided a rifaximin complex as described above for use in the treatmentof travelers' diarrhea caused by noninvasive strains of Escherichiacoli. The present invention further provides a rifaximin complex asdescribed above for use in treating bowel disease.

According to yet another aspect of the present invention, there isprovided the use of a rifaximin complex as described above for use inthe manufacture of a medicament for treating travelers' diarrhea causedby noninvasive strains of Escherichia coli as well as for treating boweldisease.

According to yet another aspect of the present invention, there isprovided a method of treating hypertension or benign prostatichyperplasia or for treating bowel disease, comprising administering to apatient in need thereof a therapeutically effective amount of rifaximincomplex as described above.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

FIG. 1—intrinsic dissolution profile of (1:2 w/w rifaximin:PVP) PVPcomplex of rifaximin of the present invention compared with that of aphysical mixture of β-rifaximin and PVP (1:2 w/w rifaximin:PVP) by anHPLC-UV method.

FIG. 2—intrinsic dissolution profile of (1:1 w/w rifaximin:PVP) PVPcomplex of rifaximin of the present invention compared with that of aphysical mixture of β-rifaximin and PVP (1:1 w/w rifaximin:PVP) by anHPLC-UV method

FIG. 3—intrinsic dissolution profile of (4:1 w/w rifaximin:PVP) PVPcomplex of rifaximin of the present invention compared with that of aphysical mixture of β-rifaximin and PVP (4:1 w/w rifaximin:PVP) by anHPLC-UV method.

FIG. 4—intrinsic dissolution profile of (10:1 w/w rifaximin:PVP) PVPcomplex of rifaximin of the present invention compared with that of aphysical mixture of β-rifaximin and PVP (10:1 w/w rifaximin:PVP) by anHPLC-UV method.

FIG. 5—intrinsic dissolution profile of (1:2 w/w rifaximin:β-CD)β-cyclodextrin complex of rifaximin of the present invention comparedwith that of a physical mixture of β-rifaximin and CD (1:2 w/wrifaximin:β-CD) by an HPLC-UV method.

FIG. 6 indicates intrinsic dissolution profile of (1:1 w/wrifaximin:β-CD) β-cyclodextrin complex of rifaximin of the presentinvention compared with that of a physical mixture of β-rifaximin and CD(1:1 w/w rifaximin:β-CD) by an HPLC-UV method

FIG. 7 indicates intrinsic dissolution profile of (4:1 w/wrifaximin:β-CD) β-cyclodextrin complex of rifaximin of the presentinvention compared with that of a physical mixture of β-rifaximin and CD(4:1 w/w rifaximin:β-CD) by an HPLC-UV method.

FIG. 8 indicates intrinsic dissolution profile of (10:1 w/wrifaximin:β-CD) β-cyclodextrin complex of rifaximin of the presentinvention compared with that of a physical mixture of β-rifaximin and CD(10:1 w/w rifaximin:β-CD) by an HPLC-UV method.

FIG. 9 indicates an X-ray powder diffractogram (XRD) of a β-cyclodextrincomplex of rifaximin at 1:1 w/w concentration.

FIG. 10 indicates an X-ray powder diffractogram (XRD) of (10:1 w/wrifaximin:PVP) a PVP complex of rifaximin.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certainpreferred and optional embodiments, so that various aspects thereof maybe more fully understood and appreciated.

The present invention provides a form of rifaximin with enhancedsolubility and stability. This form of rifaximin comprises a complex ofrifaximin with a complexing agent. The complexing agents used in thepresent invention include more particularly a polyvinyl pyrrolidone or acyclodextrin.

There is also provided by the present invention a process for preparingthe rifaximin-complexing agent complex of the present invention, theprocess comprising:

a) dissolving the rifaximin in a suitable solvent;b) adding the complexing agent to the rifaximin solution either as suchor in the form of solution to form a mixture;c) isolating the complex, for example by concentrating the reaction massobtained in stepb) and further drying to obtain the complex.

The rifaximin used in the process of the present invention may beobtained by any one of the methods disclosed in the prior art. Forexample, the rifaximin used in the process of the present invention maybe in the polymorphic form α, β, γ, δ or ε. In a preferred embodiment ofthe present invention, the rifaximin used is in the β-form. The β-formof rifaximin is the least soluble known form of rifaximin.

The solvent used may be selected from ethers, alcohols, esters,aldehydes, halogenated solvents, hydrocarbons and combinations thereof.

In the process of the present invention, the complexing agent used maybe selected from polyvinyl pyrrolidone (PVP) or cyclodextrin (CD).

Polyvinyl pyrrolidone (PVP, also known as “povidone”) is commerciallyavailable as a white powder of a given molecular weight. Generally, themolecular weights of PVP polymers are given by their K-values, e.g.,K-15 to K-90. The K-value indicates the average molecular weight rangingfrom 20,000 to 1,000,000. A preferred PVP is K-30, typically having amolecular weight of about 40,000. An unusual property of PVP is itssolubility in water as well as in various organic solvents.

In the process of the present invention, the PVP may be selected fromthe group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80,K-90 and K-120. Preferably, K-25, K-30, K-90, and most preferably K-30.

In the process of the present invention, the cyclodextrin used to formthe complex may be in any form of cyclodextrin, including α-cyclodextrinhaving 6 glucose units, β-cyclodextrin having 7 glucose units, orγ-cyclodextrin having 8 glucose units. The cyclodextrin may also be inanhydrous or hydrated form. The preferred cyclodextrin isβ-cyclodextrin.

The complexing agent may be added as such or as a solution in a suitablesolvent. The amount of rifaximin that can be encapsulated is directlyrelated to the molecular weight of the rifaximin.

In some embodiments, one mole of complexing agent encapsulates one moleof rifaximin. Preferably, the amounts of rifaximin and complexing agentused in the formulation are typically sufficient to provide the desiredtherapeutic effect. On a weight basis, the ratio between rifaximin andcomplexing agent in the given composition (termed “w/w”), ranges from20:1 to 1:20, preferably from 10:1 to 1:2. Typically, the ratio ofrifaximin to complexing agent ranges from 4:1 to 1:2. The ratio may be1:1.

The solvent may be removed rapidly and completely by vacuum drying orvacuum evaporation. In an embodiment, the solvent may be removed byspray drying to yield the rifaximin complex. In another embodiment, therifaximin complex may be obtained freeze drying. In yet anotherembodiment, the rifaximin complex may be isolated by microwave treatmenttechniques.

According to a third aspect of the present invention, there is provideda rifaximin complex which enhances at least one of the following:—

a) stabilization of rifaximin against degradation (e.g. hydrolysis,oxidation, etc)b) enhancement of water solubility of rifaximinc) better dissolutiond) free flowing and non-hygroscopic rifaximine) modified solubility, delivery or performancef) safe handling of rifaximin

The rifaximin complex of the present invention is not a simple physicalmixture of the ingredients. This rifaximin complex is superior to theconventional free base of rifaximin, for example in terms of storagestability.

Further, it was observed that the use of a complexing agent as anexcipient in the formulation enhances solubility to some extent but theformation of a complex with rifaximin enhances solubility much more thanmixing it physically as an excipient. Further, the aqueous solubility ofthe rifaximin complex with cyclodextrin or PVP is found to be greaterthan the aqueous solubility of rifaximin. The enhanced solubility of thecomplex can further increase dissolution rate as shown in FIGS. 1 to 8and thus makes these complexes more bio-available in the body. Thisincrease in bioavailability and stability of the complex further allowsfor smaller doses to achieve the desired therapeutic effect compared toa larger dose of rifaximin alone. Further, these complexes avoidinterconversion of crystalline forms of rifaximin. In addition, thesecomplexes can be used to reduce or prevent gastrointestinal and ocularirritation, to reduce or eliminate unpleasant smells or tastes, as wellas to prevent drug-drug or drug-additive interactions.

According to another aspect of the present invention, there is provideda rifaximin complex characterized by having an intrinsic dissolutionprofile as shown in any one of FIGS. 1 to 8.

To measure the intrinsic dissolution of a rifaximin complex, for examplea rifaximin-PVP complex or a rifaximin-CD complex, rifaximin sampleswere measured to compare the influence of the different parametersettings. At appropriate time intervals, an automated sample collectorremoves aliquots from the dissolution medium for analysis. The timeinterval for sampling can vary, for example, from 2 to 30 minutes,depending on the properties of the drug and dissolution medium used.Suitable dissolution equipment for these operations includes LAB INDIADISSO 2000.

The complexes may be used in a variety of applications. In anembodiment, the composition of the present invention is in the form of atablet, a capsule or a liquid oral. The composition may furtheroptionally include additional components to enhance or achieve thedesired therapeutic effect of rifaximin. Examples of such componentsinclude, but are not limited to surfactants, excipients, disintegratingagents, binders, lubricants, dispersing agents, thickening agents.

The present invention will now be further illustrated by the followingexamples, which do not limit the scope of the invention in any way.

Example 1 Preparation of Rifaximin-PVP Complex (1:2 w/w Ratio)Preparation 1

2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. 4 g ofPVP K-30 was dissolved in 40 ml ethanol. The solution of PVP K-30 wasadded to the rifaximin solution and stirred. The reaction mass wasconcentrated under vacuum at 35° C. till dryness and then driedcompletely at 30-35° C. for 24 hours to get 5.4 g rifaximin-PVP complex.

Preparation 2

5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. Thereaction mass was heated to 35° C. and 10 g of PVP K-30 was added to therifaximin solution and stirred. The reaction mass was concentrated undervacuum at 35° C. till dryness and then dried completely at 30-35° C. for24 hours to get 13 g rifaximin-PVP complex.

Example 2 Preparation of Rifaximin-PVP Complex (1:1 w/w Ratio)Preparation 1

2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. 2 g ofPVP K-30 was dissolved in 20 ml of ethanol. The solution of PVP K-30 wasadded to the rifaximin solution and stirred. The reaction mass wasconcentrated under vacuum at 35° C. till dryness and then driedcompletely at 30-35° C. for 24 hours to get 3.1 g rifaximin-PVP complex.

Preparation 2

5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. Thereaction mass was heated to 35° C. and 5 g of PVP K-30 was added to therifaximin solution and stirred. The reaction mass was concentrated undervacuum at 35° C. till dryness and then dried completely at 30-35° C. for24 hours to get 8.8 g rifaximin-PVP complex.

Example 3 Preparation of Rifaximin-PVP Complex (4:1 w/w Ratio)Preparation 1

10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35° C. Asolution of PVP K-30 was prepared by dissolving 2.5 g of PVP K-30 in 25ml of ethanol. This solution was added to the rifaximin solution at30-35° C. The reaction mass was stirred, concentrated to dryness undervacuum at 30-35° C. and then dried completely at 70° C. for 24-30 hoursto get 12.5 g rifaximin-PVP complex.

Preparation 2

5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. Thereaction mass was heated to 35° C. and 1.25 g of PVP K-30 was added tothe rifaximin solution and stirred. The reaction mass was concentratedunder vacuum at 35° C. till dryness and then dried completely at 30-35°C. for 24 hours to get 5.5 g rifaximin-PVP complex.

Example 4 Preparation of Rifaximin-PVP Complex (10:1 w/w Ratio)Preparation 1

10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35° C. Asolution of PVP K-30 was prepared by dissolving 1 g of PVP K-30 in 15 mlof ethanol. The solution was added to the rifaximin solution. Thereaction mass was stirred at 30-35° C., concentrated to dryness undervacuum at 30-35° C. and then dried completely at 30-35° C. for 24-30hours to get 10.3 g rifaximin-PVP complex.

Preparation 2

5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30° C. Thereaction mass was heated to 35° C. and 0.5 g of PVP K-30 was added tothe rifaximin solution and stirred. The reaction mass was concentratedunder vacuum at 35° C. till dryness and then dried completely at 30-35°C. for 24 hours to get 5.0 g rifaximin-PVP complex.

Example 5 Preparation of the Rifaximin-β-Cyclodextrin Complex (1:2 w/wRatio) Preparation 1

2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. To thissolution 4 g of β-cyclodextrin was added and stirred. The reaction masswas concentrated under vacuum at 35° C., stripped with 20 ml of ethanol.This residue was concentrated to dryness and dried under vacuum at30-35° C. for 20-24 hours to get 5.1 g rifaximin-β cyclodextrin complex.

Preparation 2

4 g of rifaximin was dissolved in 60 ml of ethanol at 25-30° C. Thereaction mass was heated to 35° C. and 8 g of β-cyclodextrin was addedto the rifaximin solution and stirred. The reaction mass wasconcentrated under vacuum at 35° C. till dryness and then driedcompletely at 30-35° C. for 24 hours to get 10.7 g rifaximin-βcyclodextrin complex.

Example 6 Preparation of Rifaximin β-Cyclodextrin Complex (1:1 w/wRatio)

2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30° C. To thissolution 2 g of β-cyclodextrin was added and stirred. The reaction masswas concentrated under vacuum at 35° C. and then dried completely at30-35° C. for 20-24 hours to get 2.8 g rifaximin-β cyclodextrin complex.

Example 7 Preparation of the Rifaximin-6-Cyclodextrin Complex (4:1 w/wRatio)

7 g of rifaximin was dissolved in 100 ml of ethanol at 30-35° C. To thissolution 1.75 g of β-cyclodextrin was added and stirred. The reactionmass was stirred, concentrated to dryness under vacuum at 30-35° C. andthen dried completely at 30-35° C. for 24-30 hours to get 8.1 grifaximin-β cyclodextrin complex.

Example 8 Preparation of the Rifaximin-β-Cyclodextrin Complex (10:1 w/wRatio)

7 g of rifaximin was dissolved in 100 ml of ethanol at 30-35° C. To thissolution 0.7 g of β-cyclodextrin was added and stirred. The reactionmass was stirred, concentrated to dryness under vacuum at 30-35° C. andthen dried completely at 30-35° C. for 24-30 hours to get 6.75 grifaximin-β cyclodextrin complex.

Comparative Intrinsic Dissolution Study Example 9 Preparation of TabletGeneral Process for Preparing Tableting Mixture Comprising RifaximinComplex:—

A tableting mixture (100 mg) comprising solely rifaximin complexprepared according to any of the examples 1 to 8 (i.e. with noexcipients) was prepared and compressed to a pellet using a manual handpress operating at a compression pressure of 2.5 tones for 5 minutes.

General Process for Preparing Tableting Mixture Comprising a PhysicalMixture of Rifaximin and Complexing Agent:—

Similarly a tableting mixture (100 mg) comprising a solely physicalmixture of rifaximin and complexing agent in the proportionate ratio(i.e. with no excipients) was prepared by mixing the rifaximin andcomplexing agent in the desired ratio in a mortar and pestle for 5minutes and compressing to a pellet using a manual hand press operatingat a compression pressure of 2.5 tones for 5 minutes.

Example 10 Preparation of 1:2 Physical Mixture Comprising Rifaximin andPVPK (where PVPK is PVP K-30)

100 mg of input API of rifaximin and 200 mg of PVPK were mixed uniformlyand used for pellet preparation. (Inj volume: 30 μl)

In-vitro dissolution studies were performed on the 100 mg pellet in aLAB INDIA DISSO 2000.

The pellet was fixed in a PFTE holder, such that only the pellet surfacecame into contact with the dissolution medium. The PFTE loaded holderwas placed in the dissolution vessel containing 900 ml of 0.1M of sodiumdihydrogen phosphate having pH 7.4 at 37±0.5° C. Two pellets weremeasured for each run of the design of the experiments. Stirring wasperformed with a paddle rotating at 100 rpm. The dissolution wasfollowed up to 1440 min and the concentration of active ingredient,rifaximin, dissolved in the test medium was determined by removingsamples of 10 ml at the specified time.

The concentration of rifaximin complex was quantified by HPLC UV methodat a maximum wavelength of 300 nm under the conditions as specifiedbelow:

Mobile Phase Buffer:Acetonitrile: 45:55 Buffer 0.025M Sodium dihydrogenphosphate. The pH adjusted to 3.0 with orthophosphoric acid ColumnZorbax SB-phenyl, 4.6 mm, 5 μm Column Temp 25° C. Flow 1.0 ml/minInjection Volume 30 μL Diluent Buffer:Acetonitrile: 1:1 StandardPreparation 25 mg standard dissolved to 25 ml with diluent. 5 ml of thissolution diluted to 50 ml with dissolution medium.

The percentage of rifaximin released from the PVPK complex (1:2 w/w) aswell as from the physical mixture (1:2 w/w) were plotted against time asshown in FIG. 1. The intrinsic dissolution rate was derived from theslope of this curve. Table 1 shows the results in tabular form.

TABLE 1 TIME IN (1:2) PVPK MINS (1:2) PVP COMPLEX PHYSICAL MIXTURE 150.65 0.12 30 0.97 0.11 45 1.92 0.14 60 2.62 0.19 120 6.42 0.42 180 9.781.34 240 11.51 3.10 360 15.98 10.09 480 20.08 15.48 600 26.79 18.02 72030.40 21.20 840 31.25 21.10 960 32.40 22.78 1080 31.40 23.65 1200 30.8622.66

Example 11 Preparation of 1:1 Physical Mixture Comprising Rifaximin andPVPK

100 mg of input API of rifaximin and 100 mg PVPK respectively were mixeduniformly and used for pellet preparation. (Inj volume: 20 μl)

The percentage of rifaximin released from the PVP complex (1:1 w/w) aswell as from the physical mixture (1:1 w/w) were plotted against time asshown in FIG. 2. The intrinsic dissolution rate was derived from theslope of this curve. Table 2 shows the results in tabular form.

TABLE 2 TIME IN (1:1) PVP MINS (1:1) PVP COMPLEX PHYSICAL MIXTURE 150.86 0.19 30 1.71 0.16 45 2.54 0.19 60 3.39 0.20 120 7.15 0.37 180 10.390.94 240 13.21 2.22 360 18.45 5.69 480 23.42 8.33 600 28.48 10.72 72033.64 12.67 840 38.94 14.23 960 42.13 15.28 1080 42.46 16.17 1200 42.2616.99

Example 12 Preparation of 4:1 Physical Mixture Comprising Rifaximin andPVPK

100 mg of input API of rifaximin and 25 mg PVPK were mixed uniformly andused for pellet preparation. (Inj volume: 15 μl)

The percentage of rifaximin released from the PVP complex (4:1 w/w) aswell as from the physical mixture (4:1 w/w) were plotted against time asshown in FIG. 3. The intrinsic dissolution rate was derived from theslope of this curve. Table 3 shows the results in tabular form.

TABLE 3 TIME IN (4:1) PVPK MINS (4:1) PVPK COMPLEX PHYSICAL MIXTURE 151.37 0.17 30 2.68 0.27 45 5.65 0.48 60 7.09 0.77 120 13.22 1.29 18018.01 2.06 240 20.34 3.09 360 29.76 7.99 480 37.20 15.86 600 41.53 22.53720 49.81 27.01 840 54.99 29.87 960 60.41 32.22 1080 66.82 35.53 120071.08 33.83

Example 13 Preparation of 10:1 Physical Mixture Comprising Rifaximin andPVPK

100 mg of input API of rifaximin and 10 mg PVPK were mixed uniformly andused for pellet preparation. (Inj volume: 10 μl)

The percentage of rifaximin released from the PVP complex (10:1 w/w) aswell as from the physical mixture (10:1 w/w) were plotted against timeas shown in FIG. 4. The intrinsic dissolution rate was derived from theslope of this curve. Table 4 shows the results in tabular form.

TABLE 4 TIME IN (10:1) PVPK MINS (10:1) PVPK COMPLEX PHYSICAL MIXTURE 151.01 0.41 30 1.81 0.38 45 2.63 0.44 60 3.41 0.54 120 6.50 0.94 180 9.651.34 240 12.76 1.83 360 18.78 3.86 480 24.96 7.32 600 30.90 10.83 72036.68 13.82 840 42.74 16.43 960 48.70 18.73 1080 53.95 21.13 1200 59.0223.50 1320 63.10 25.54 1440 65.72 27.08

Example 14

Example 10 was repeated using Beta cyclodextrin instead of PVPK and thepercentage of rifaximin released from the CD complex (1:2 w/w) as wellas from the physical mixture (1:2 w/w) were plotted against time asshown in FIG. 5. The intrinsic dissolution rate was derived from theslope of this curve. Table 5 shows the results in tabular form.

TABLE 5 (1:2) BETA (1:2) BETA TIME IN CYCLODEXTRIN CYCLODEXTRIN MINSCOMPLEX PHYSICAL MIXTURE 15 0.48 0.17 30 0.82 0.25 45 1.35 0.35 60 2.050.48 120 4.83 0.80 180 7.67 1.33 240 9.87 1.81 360 15.23 2.82 480 20.214.14 600 23.58 4.84 720 25.33 6.43 840 24.97 6.97 960 25.67 7.19 108026.37 8.80 1200 26.37 8.50

Example 15

Example 11 was repeated using Beta cyclodextrin instead of PVPK and thepercentage of rifaximin released from the CD complex (1:1 w/w) as wellas from the physical mixture (1:1 w/w) were plotted against time asshown in FIG. 6. The intrinsic dissolution rate was derived from theslope of this curve. Table 6 shows the results in tabular form.

TABLE 6 (1:1) BETA (1:1) BETA TIME IN CYCLODEXTRIN CYCLODEXTRIN MINSCOMPLEX PHYSICAL MIXTURE 15 0.85 0.17 30 1.46 0.29 45 2.29 0.40 60 3.040.53 120 6.02 0.95 180 9.07 1.39 240 12.08 1.89 360 17.88 2.86 480 23.664.97 600 29.22 4.93 720 34.43 5.88 840 37.54 6.69 960 38.32 7.27 108038.49 7.82 1200 38.66 8.32

Example 16

Example 12 was repeated using Beta cyclodextrin instead of PVPK and thepercentage of rifaximin released from the CD complex (4:1 w/w) as wellas from the physical mixture (4:1 w/w) were plotted against time asshown in FIG. 7. The intrinsic dissolution rate was derived from theslope of this curve. Table 7 shows the results in tabular form.

TABLE 7 (4:1) BETA TIME IN (4:1)BETA CYCLODEXTRIN MINS CYCLODEXTRINPHYSICAL MIXTURE 15 1.09 0.52 30 2.85 0.64 45 3.54 0.81 60 6.29 1.01 12010.61 1.91 180 15.88 2.33 240 18.66 3.09 360 26.97 3.64 480 34.74 4.28600 42.07 4.36 720 47.29 8.14 840 54.05 8.92 960 60.82 11.09 1080 66.1310.90 1200 68.04 11.39

Example 17

Example 13 was repeated using Beta cyclodextrin instead of PVPK and thepercentage of rifaximin released from the CD complex (10:1 w/w) as wellas from the physical mixture (10:1 w/w) were plotted against time asshown in FIG. 8. The intrinsic dissolution rate was derived from theslope of this curve. Table 8 shows the results in tabular form.

TABLE 8 (10:1) BETA TIME IN (10:1) BETA CYCLODEXTRIN MINS CYCLODEXTRINPHYSICAL MIXTURE 15 0.96 0.28 30 1.78 0.38 45 2.58 0.49 60 3.36 0.56 1206.65 1.00 180 9.84 1.37 240 12.87 1.78 360 19.00 2.58 480 25.52 3.41 60031.48 4.22 720 37.35 4.92 840 43.19 5.65 960 46.88 6.34 1080 48.74 7.011200 49.97 7.67 1320 49.81 8.28 1440 50.01 8.86

The results were reported on an average of 2 results each.

When compared with a physical mixture of rifaximin with a complexingagent, the rifaximin complex exhibited a superior rate of dissolution asshown in Tables 9 and 10 below.

The percentage of actual release of rifaximin is calculated from thecharacteristics data obtained in the FIGS. 1 to 8. The formula forcalculating the percentage of actual release of rifaximin from thecomplex is given below:

${\% \mspace{14mu} {of}\mspace{14mu} {actual}\mspace{14mu} {release}\mspace{14mu} {of}\mspace{14mu} {rifaximin}} = {\frac{\% \mspace{14mu} {relese}\mspace{14mu} {of}\mspace{14mu} {rifaximin}\mspace{14mu} {from}\mspace{14mu} {the}\mspace{14mu} {complex}}{{wt}\mspace{14mu} \% \mspace{14mu} {of}\mspace{14mu} {rifaximin}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {complex}} \times 100}$

TABLE 9 The Actual release of Rifaximin from Rifaximin-PVP complexcompared with physical mixture:- % Rifaximin Content of complexing %Rifaximin released from released from agent (w/w) PVP complex Physicalmixture 1:2 92.67 68.05 1:1 84.52 33.98 4:1 88.85 42.29 10:1  73.0030.09

The above data shows that the PVP complex has more advantage over aphysical mixture. This advantage is maximum at lower concentration ofPVP i.e. when ratio is 10:1 (73:30), whereas at high concentration i.e.when ratio is 1:2 or 33.3% the advantage is about 1.36 times(92.67:68.05)

TABLE 10 The Actual release of Rifaximin from Rifaximin-CD complexcompared with physical mixture:- % Rifaximin Content of complexing %Rifaximin released from released from agent (w/w) CD complex Physicalmixture 1:2 79.18 25.52 1:1 77.32 16.64 4:1 85.00 14.23 10:1  55.55 9.84

The above data shows that, the CD complex has more advantage over aphysical mixture. This advantage is maximum at a lower concentration ofCD i.e. when the ratio is 10:1 (55.55:9.84), whereas at highconcentration i.e. when ratio is 1:2 or 33.3% the advantage is about 3.1times (79.18: 25.52)

These results further proved that rifaximin complex had been formedafter this technique.

It will be appreciated that the invention may be modified within thescope of the appended claims.

1. A complex comprising rifaximin and a complexing agent, wherein thecomplexing agent is a polyvinyl pyrrolidone (PVP) or a cyclodextrin,with the proviso that the complexing agent is not hydroxybutenylcyclodextrin or a derivative thereof.
 2. A complex according to claim 1,wherein the complexing agent is a PVP having a K-value ranging from K-15to K-90.
 3. A complex according to claim 2, wherein the complexing agentis a PVP selected from the group consisting of PVP K-12, K-15, K-17,K-25, K-30, K-60, K-80, K-90 and K-120.
 4. A complex according to claim3, wherein the complexing agent is K-30.
 5. A complex according to claim1, wherein the complexing agent is a cyclodextrin selected from thegroup consisting of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. 6.A complex according to claim 5, wherein the cyclodextrin isβ-cyclodextrin.
 7. A complex according to claim 1, characterized byhaving an intrinsic dissolution profile as shown in any one of FIGS. 1to
 8. 8. A complex according to claim 1, wherein the complex is in theamorphous form.
 9. A complex according to any preceding claim, whereinthe ratio of rifaximin to complexing agent ranges from 20:1 w/w to 1:20w/w.
 10. A complex according to claim 9, wherein the ratio of rifaximinto complexing agent ranges from 10:1 w/w to 1:2 w/w.
 11. A process forpreparing a complex of rifaximin and a complexing agent according to anypreceding claim, the process comprising a) dissolving rifaximin in asolvent; b) adding the complexing agent to the solution of rifaximin;and c) isolating the complex from the solution.
 12. A process accordingto claim 11, wherein the complexing agent is added to the rifaximinsolution as such or in the form of a solution with a solvent.
 13. Aprocess according to claim 11 or 12, wherein the solvent for therifaximin is selected from the group consisting of an ether, an alcohol,an ester, an aldehyde, a halogenated solvent, a hydrocarbon and mixturesthereof.
 14. A process according to claim 11, 12 or 13, wherein thecomplexing agent is added to the rifaximin solution in the form of asolution with a solvent, and the complexing agent solvent is selectedfrom the group consisting of an ether, an alcohol, an ester, analdehyde, a halogenated solvent, a hydrocarbon and mixtures thereof. 15.A process according to claim 13 or 14, wherein the solvent for therifaximin and/or the solvent for the complexing agent is ethanol.
 16. Aprocess according to any one of claims 11 to 15, wherein the isolationcomprises concentrating the reaction mass obtained in step b), anddrying to obtain the isolated complex.
 17. A complex of rifaximin and acomplexing agent according to any one of claims 1 to 10 preparedaccording to any one of claims 11 to
 16. 18. A pharmaceuticalcomposition comprising a complex according to any one of claim 1 to 10or 17, together with one or more pharmaceutically acceptable excipients.19. A complex according to any one of claim 1 to 10 or 17, or acomposition according to claim 18, for use in medicine.
 20. A complexaccording to any one of claim 1 to 10 or 17, or a composition accordingto claim 18, for use in treating bowel related disorders.
 21. A complexaccording to any one of claim 1 to 10 or 17, or a composition accordingto claim 18, for use according to claim 20, wherein the bowel relateddisorder is selected from the group consisting of irritable bowelsyndrome, diarrhea, traveler's diarrhea, microbe associated diarrhea,Crohn's disease, chronic pancreatitis, pancreatic insufficiency and/orcolitis.
 22. A method of treating diarrhea, comprising administering atherapeutically effective amount of a complex according to any one ofclaim 1 to 10 or 17, or a composition according to claim 18, to apatient in need thereof.
 23. A complex substantially as herein describedwith reference to the Examples.
 24. A process substantially as hereindescribed with reference to the Examples.